Recent key scientific discoveries have identified oligomers of the protein Abeta 42 as the synaptotoxic culprits in the Alzheimer's disease process. With increasing age, decline in brain levels of Abeta binding and clearance proteins and elevations in enzyme activity responsible for producing Abeta combine to produce an elevation of monomeric Abeta 42 levels. The hydrophobic C-terminus of this peptide then self-associates to form metastable oligomers that bind with high affinity to receptors located on a subset of neurons. Once bound, synaptotoxic Abeta oligomers alter glutamate receptor trafficking to the plasma membrane and inhibit long term potentiation, resulting in transient regression of spines, synapse loss and memory deficits (reviewed in Catalano et al., '06, Li et al., '10). Blocking Abeta oligomer effects is expected to prevent these memory deficits and slow or reverse neurodegeneration and Alzheimer's disease progression in humans. We have discovered first-in-class selective high affinity receptor antagonists that compete with human AD patient-derived oligomers for access to receptors that mediate synaptotoxicity, completely eliminate synapse loss and restore memory to normal in transgenic animals. These small molecules have excellent plasma stability and blood-brain- barrier permeability, but exhibit limited oral bioavailability due to oxidation by liver enzymes (first pass metabolism). While further preclinical development of these analogs is possible via alternate routes of systemic administration, improved oral bioavailability and oral formulation will significantly improve patiet compliance and increase the numbers of patients who could be helped by this therapeutic strategy. We propose to optimize the oral bioavailability of the CT0109 series by synthesis and testing of analogs designed to improve metabolic stability. Successful advancement of an orally bioavailable candidate could significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment currently exists. PUBLIC HEALTH RELEVANCE: Abeta oligomers trigger synaptic dysfunction and lead to the cognitive decline in MCI and early AD. Prolonged oligomer exposure leads to more severe synaptotoxicity, memory deficits and accumulated pathology. Therapeutics targeting oligomers should block and potentially reverse disease symptoms and progress. Cognition Therapeutics has discovered first-in-class high affinity receptor antagonists that compete with oligomers for access to neuronal receptors that mediate synaptotoxicity, completely eliminate synapse loss and restore memory to normal in transgenic animals. The requested funding will enable optimization of these promising molecules for oral administration, facilitating their advancement to IND-enabling preclinical studies and eventual clinical trials. Such an optimized IND Abeta oligomer receptor antagonist candidate would be among the first small molecule drugs to reverse AD and MCI symptoms and block disease progression.